Trial Information

I. To assess the activity of MK-2206 in patients with recurrent grade 2 or 3
platinum-resistant high-grade serous ovarian, fallopian tube, or peritoneal cancer, as
measured by the frequency of patients experiencing an objective tumor response by Response
Evaluation Criteria In Solid Tumors (RECIST) criteria or who survive progression-free for at
least 6 months after initiation of therapy.

SECONDARY OBJECTIVES:

I. To assess the duration of progression-free and overall survival following initiation of
therapy with MK-2206 in the cohort of patients enrolled on this study.

II. To determine the toxicities of MK-2206, as assessed by the active version of the
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0
III. To explore the association between select biomarkers and response to MK-2206 (as
assessed by objective tumor response, progression-free survival, and overall survival) IV.
To explore the development of feedback loop activation and target inhibition with MK-2206
via analysis of pre-treatment and post-treatment biopsies in select patients enrolled in the
trial.

OUTLINE:

MK-2206 will be taken orally once a week for four weeks (one cycle). Treatment will continue
for as long as a subject is benefiting from the study drug.

During each cycle subjects will have a physical exam, blood samples and an electrocardiogram
(EKG) (first 2 cycles). Every 2 cycles a computed tomography (CT) scan or magnetic resonance
imaging (MRI) of chest, stomach area, and pelvis will be performed. Optional tumor biopsies
may be performed.

Inclusion Criteria:

- Participants must have histologically or cytologically confirmed high grade (grade 2
or 3) serous ovarian, fallopian tube, or primary peritoneal cancer; participants with
mixed histology are eligible if the serous component is the dominant histological
subtype

- Participants must have measurable disease as defined by RECIST 1.1 criteria

- Participants must have evidence of a defect in the PI3K/AKT pathway, defined by A)
evidence of loss of PTEN by immunohistochemistry in a CLIA-certified assay or B)
documentation of PIK3CA or AKT mutation in a CLIA-certified assay; for patients
without prior CLIA-certified evidence of a PI3K/AKT pathway defect, PTEN testing will
be performed by immunohistochemistry in a CLIA-certified assay; availability of a
formalin fixed paraffin embedded (FFPE) block of cancer tissue from the original or
most recent biopsy must be available for mutational and immunohistochemical analysis

- Prior therapy:

- Prior chemotherapy must have included a first-line platinum-based regimen with
or without consolidation chemotherapy

- Patients may have received up to 2 lines of therapy (including cytotoxic or
biological and/or targeted therapies) in the recurrent setting

- Prior hormonal therapy is acceptable and will not count as an additional line of
therapy

- Toxicities of prior therapy (excepting alopecia) should be resolved to less than or
equal to grade 1 as per NCI-CTCAE v4.0

- Patients must be able to tolerate oral medications and not have gastrointestinal
illnesses that would preclude absorption of MK-2206

- The effects of MK-2206 on the developing human fetus are unknown; for this reason,
women of child-bearing potential must agree to use adequate contraception (hormonal
or barrier method of birth control; abstinence) prior to study entry and for the
duration of study participation; should a woman become pregnant or suspect she is
pregnant while participating in this study, she should inform her treating physician
immediately

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Participants who exhibit any of the following conditions at screening will not be
eligible for admission into the study

- Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered to grade 1 or less (excepting alopecia) due to agents administered more
than 4 weeks earlier

- Participants may not be receiving any other study agents

- Participants with known brain metastases should be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to MK-2206

- Participants receiving any medications or substances that are strong inhibitors or
inducers of CYP450 3A4 are ineligible; lists including medications and substances
known or with the potential to interact with the CYP450 3A4 isoenzymes are provided
in Appendix C; if the participant is taking any agent known to affect or with the
potential to affect CYP450 3A4 isoenzymes, this should be discussed with the overall
PI

- Preclinical studies demonstrated the potential of MK-2206 for induction of
hyperglycemia in all preclinical species tested; patients with diabetes or at risk
for hyperglycemia are eligible for this study, but the hyperglycemia should be well
controlled on oral agents before the patient enters the trial; a fasting serum
glucose of > 130 mg/dL or a HgbA1c > 7.5 mg/dL will exclude patients from entry on
study; patients requiring insulin for control of their hyperglycemia are excluded
from entry on this study

- Preclinical studies indicated transient changes in QTc interval during MK-2206
treatment; prolongation of QTc interval is potentially a safety concern while on
MK-2206 therapy; cardiovascular: baseline QTcF > 450 msec (male) or QTcF > 470 msec
(female) will exclude patients from entry on study; a list of medications that may
cause QTc interval prolongation are listed in Appendix D, and should be avoided by
patients entering on trial

- Due to a high incidence of bradycardia by Holter monitor, preexisting significant
heart block or baseline bradycardia due to cardiac disease will exclude patients from
treatment with MK-2206

- Pregnant women are excluded from this study because MK-2206 is an agent with the
potential for teratogenic or abortifacient effects; because there is an unknown but
potential risk of adverse events in nursing infants secondary to treatment of the
mother with MK-2206, breastfeeding should be discontinued if the mother is treated
with MK-2206; these potential risks may also apply to other agents used in this study

- Individuals with a history of a different malignancy are ineligible except for the
following circumstances; individuals with a history of other malignancies are
eligible if they have been disease-free for at least 5 years and are deemed by the
investigator to be at low risk for recurrence of that malignancy; individuals with
the following cancers are eligible if diagnosed and treated within the past 5 years:
breast cancer in situ, cervical cancer in situ, and basal cell or squamous cell
carcinoma of the skin

- Human immunodeficiency virus (HIV)-positive individuals on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
MK-2206; iIn addition, these individuals are at increased risk of lethal infections
when treated with marrow-suppressive therapy; appropriate studies will be undertaken
in participants receiving combination antiretroviral therapy when indicated

- Patients may not use natural herbal products or other "folk remedies" while
participating in this study

Outcome Measure:

Outcome Description:

If 4 or more of the final set of 29 patients demonstrate a response, then the null hypothesis H0: ≤5% can be rejected in favor of the alternative hypothesis H1: ≥ 20% with an alpha of 0.05 and beta of 0.20 (i.e., 80% power). In this case, the anti-tumor effect of MK-2206 in this population will be considered interesting and worthy of further investigation.

Outcome Time Frame:

Up to 3 years

Safety Issue:

No

Principal Investigator

Joyce Liu

Investigator Role:

Principal Investigator

Investigator Affiliation:

Dana-Farber Cancer Institute

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2013-00549

NCT ID:

NCT01283035

Start Date:

April 2011

Completion Date:

Related Keywords:

Ovarian Sarcoma

Recurrent Fallopian Tube Cancer

Recurrent Ovarian Epithelial Cancer

Recurrent Primary Peritoneal Cavity Cancer

Peritoneal Neoplasms

Fallopian Tube Neoplasms

Neoplasms, Glandular and Epithelial

Ovarian Neoplasms

Sarcoma

Name

Location

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